Cluster Subcutaneous Allergen Specific Immunotherapy for the Treatment of Allergic Rhinitis: A Systematic Review and Meta-Analysis

Background

Although allergen specific immunotherapy (SIT) represents the only immune- modifying and curative option available for patients with allergic rhinitis (AR), the optimal schedule for specific subcutaneous immunotherapy (SCIT) is still unknown. The objective of this study is to systematically assess the efficacy and safety of cluster SCIT for patients with AR.

Methods

By searching PubMed, EMBASE and the Cochrane clinical trials database from 1980 through May 10th, 2013, we collected and analyzed the randomized controlled trials (RCTs) of cluster SCIT to assess its efficacy and safety.

Results

Eight trials involving 567 participants were included in this systematic review. Our meta-analysis showed that cluster SCIT have similar effect in reduction of both rhinitis symptoms and the requirement for anti-allergic medication compared with conventional SCIT, but when comparing cluster SCIT with placebo, no statistic significance were found in reduction of symptom scores or medication scores. Some caution is required in this interpretation as there was significant heterogeneity between studies. Data relating to Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) in 3 included studies were analyzed, which consistently point to the efficacy of cluster SCIT in improving quality of life compared to placebo. To assess the safety of cluster SCIT, meta-analysis showed that no differences existed in the incidence of either local adverse reaction or systemic adverse reaction between the cluster group and control group.

Conclusion

Based on the current limited evidence, we still could not conclude affirmatively that cluster SCIT was a safe and efficacious option for the treatment of AR patients. Further large-scale, well-designed RCTs on this topic are still needed.     

Allergen Microarray Indicates Pooideae Sensitization in Brazilian Grass Pollen Allergic Patients

Background

Grass pollen, in particular from Lolium multiflorum is a major allergen source in temperate climate zones of Southern Brazil. The IgE sensitization profile of Brazilian grass pollen allergic patients to individual allergen molecules has not been analyzed yet.

Objective

To analyze the IgE sensitization profile of a Brazilian grass pollen allergic population using individual allergen molecules.

Methods

We analyzed sera from 78 grass pollen allergic patients for the presence of IgE antibodies specific for 103 purified micro-arrayed natural and recombinant allergens by chip technology. IgE-ELISA inhibition experiments with Lolium multiflorum, Phleum pratense extracts and a recombinant fusion protein consisting of Phl p 1, Phl p 2, Phl p 5 and Phl p 6 were performed to investigate cross-reactivities.

Results

Within the Brazilian grass pollen allergic patients, the most frequently recognized allergens were Phl p 1 (95%), Phl p 5 (82%), Phl p 2 (76%) followed by Phl p 4 (64%), Phl p 6 (45%), Phl p 11 (18%) and Phl p 12 (18%). Most patients were sensitized only to grass pollen allergens but not to allergens from other sources. A high degree of IgE cross-reactivity between Phleum pratense, Lolium multiflorum and the recombinant timothy grass fusion protein was found.

Conclusions

Component-resolved analysis of sera from Brazilian grass pollen allergic patients reveals an IgE recognition profile compatible with a typical Pooideae sensitization. The high degree of cross-reactivity between Phleum pratense and Lolium multiflorum allergens suggests that diagnosis and immunotherapy can be achieved with timothy grass pollen allergens in the studied population.     

Greater risk of incident asthma cases in adults with Allergic Rhinitis and Effect of Allergen Immunotherapy: A Retrospective Cohort Study

Asthma and rhinitis are often co-morbid conditions. As rhinitis often precedes asthma it is possible that effective treatment of allergic rhinitis may reduce asthma progression.The aim of our study is to investigate history of allergic rhinitis as a risk factor for asthma and the potential effect of allergen immunotherapy in attenuating the incidence of asthma.Hospital-referred non-asthmatic adults, aged 18–40 years between 1990 and 1991, were retrospectively followed up until January and April 2000. At the end of follow up, available subjects were clinically examined for asthma diagnosis and history of allergen specific immunotherapy, second-hand smoking and the presence of pets in the household. A total of 436 non-asthmatic adults (332 subjects with allergic rhinitis and 104 with no allergic rhinitis nor history of atopy) were available for final analyses.The highest OR (odds ratio) associated with a diagnosis of asthma at the end of follow-up was for the diagnosis of allergic rhinitis at baseline (OR, 7.8; 95%CI, 3.1–20.0 in the model containing the covariates of rhinitis diagnosis, sex, second-hand smoke exposure, presence of pets at home, family history of allergic disorders, sensitization to Parietaria judaica; grass pollen; house dust mites; Olea europea: orchard; perennial rye; and cat allergens). Female sex, sensitization to Parietaria judaica and the presence of pets in the home were also significantly predictive of new onset asthma in the same model. Treatment with allergen immunotherapy was significantly and inversely related to the development of new onset asthma (OR, 0.53; 95%CI, 0.32–0.86).In the present study we found that allergic rhinitis is an important independent risk factor for asthma. Moreover, treatment with allergen immunotherapy lowers the risk of the development of new asthma cases in adults with allergic rhinitis.     

食物不耐受导致变态反应性皮肤病的临床观察

目的:探讨血清中14种食物特异性IgG抗体与变态反应性皮肤病的相关性.为临床诊治提供依据.方法:应用酶联免疫吸附法,检测120例变态反应性皮肤病患者(荨麻疹40例,湿疹50例,过敏性紫癜30例)血清中14种食物变应原IgG浓度,另设正常对照组20例,按疾病分组观察并比较血清检测结果.结果:120例患者14种食物变应原血清不耐受抗体IgG检测结果阳性率依次为:牛肉,鸡肉,鳕鱼,玉米,螃蟹,鸡蛋,蘑菇,牛奶,猪肉,大米,虾,大豆,西红柿,小麦.结果表明,病例中以鸡蛋、虾、螃蟹的致敏性较高(阳性率比较差别显著,P<0.0001);小麦、牛奶、西红柿和蘑菇的致敏性次之(阳性率比较差别显著,P<0.0001);牛肉、鸡肉、鳕鱼、玉米、猪肉、大米、大豆致敏性较低(阳性率比较差别显著,P<0.0001).结论:变态反应性皮肤病患者体内特异性IgG抗体阳性率高,提示与食物不耐受有关,对临床变态反应性皮肤痛的饮食指导有重要意义.检测血清食物变应原不耐受抗体IgG可以尽早发现患者的致敏食物确定疾病病因,及时将致敏食物从患者食谱中排除,降低患者食物过敏的患病率,缓解临床症状,从而降低变态反应性皮肤病的发病率.     

Induction of Allergic Responses to Peanut Allergen in Sheep

Peanut allergy is the leading cause of deaths due to food-induced anaphylaxis but despite continued research, there are currently no specific treatments available. Challenge testing is limited in patients due to the high risk of adverse reactions, emphasising the need for an appropriate animal model. In the present study we examine the induction of allergic responses in a sheep model for peanut allergy. Sheep were sensitised with peanut (PN) extract and in separate injections with ovalbumin (OVA) or house dust mite (HDM) extract. Serum PN-specific IgE responses were detected in 40–50% of immunised sheep, while only 10% (1 of 10 sheep) showed detectable OVA-specific IgE. All PN-allergic sheep tested showed an Ara h 1-specific IgE response, while four out of five allergic sheep showed an Ara h 2-specific IgE response. Animals with high serum IgE levels to HDM were also PN IgE-positive. Of the PN-sensitised animals with high PN-specific IgE, 80% also showed an immediate hypersensitivity reaction following an intradermal PN injection. This new large animal model of peanut allergy may provide a useful tool for future investigations of allergen-associated immune mechanisms and specific immunotherapy.     

Immunotherapy Reduces Allergen-Mediated CD66b Expression and Myeloperoxidase Levels on Human Neutrophils from Allergic Patients

CD66b is a member of the carcinoembryonic antigen family, which mediates the adhesion between neutrophils and to endothelial cells. Allergen-specific immunotherapy is widely used to treat allergic diseases, and the molecular mechanisms underlying this therapy are poorly understood. The present work was undertaken to analyze A) the in vitro effect of allergens and immunotherapy on cell-surface CD66b expression of neutrophils from patients with allergic asthma and rhinitis and B) the in vivo effect of immunotherapy on cell-surface CD66b expression of neutrophils from nasal lavage fluid during the spring season. Myeloperoxidase expression and activity was also analyzed in nasal lavage fluid as a general marker of neutrophil activation.

Results

CD66b cell-surface expression is upregulated in vitro in response to allergens, and significantly reduced by immunotherapy (p<0.001). Myeloperoxidase activity in nasal lavage fluid was also significantly reduced by immunotherapy, as were the neutrophil cell-surface expression of CD66b and myeloperoxidase (p<0.001). Interestingly, CD66b expression was higher in neutrophils from nasal lavage fluid than those from peripheral blood, and immunotherapy reduced the number of CD66⁺MPO⁺ cells in nasal lavage fluid. Thus, immunotherapy positive effects might, at least in part, be mediated by the negative regulation of the CD66b and myeloperoxidase activity in human neutrophils.     

Crystal Structure of the Dog Lipocalin Allergen Can f 2: Implications for Cross-reactivity to the Cat Allergen Fel d 4

The dog lipocalin allergen Can f 2 is an important cause of allergic sensitization in humans worldwide. Here, the first crystal structure of recombinant rCan f 2 at 1.45 Å resolution displays a classical lipocalin fold with a conserved Gly-Xaa-Trp motif, in which Trp19 stabilizes the overall topology of the monomeric rCan f 2. Phe38 and Tyr84 localized on the L1 and L5 loops, respectively, control access to the highly hydrophobic calyx. Although the rCan f 2 calyx is nearly identical with the aero-allergens MUP1, Equ c 1 and A2U from mouse, horse and rat, respectively, no IgE cross-reactivity was found using sera from five mono-sensitized subjects. However, clear IgE cross-reactivity was demonstrated between Can f 2 and the cat allergen Fel d 4, although they share less than 22% sequence identity. This suggests a role for these allergens in co-sensitization between cat- and dog-allergic patients.     

盐城地区未成年过敏性疾病患者吸入性过敏原IgE检测结果分析

摘要 目的：通过研究分析盐城地区未成年过敏性疾病患者吸入性过敏原特异性IgE检测结果分布变化特点,为过敏性疾病预防和临床诊疗提供科学依据。方法：自2020年1月至2021年3月期间,选择430例未成年(<18岁)过敏性疾病患者,血清检测方法采用欧蒙公司生产的过敏原特异性IgE检测试剂盒。结果：430例患者中,血清过敏原IgE阳性166例(38.60%),其中尘螨和屋尘是主要的吸入性过敏原。血清IgE阳性率男性39%,女性36% (P>0.05),中学组女性阳性率（61.11 %）高于男性（45.83 %）（P<0.05）。不同年龄组间IgE阳性率有统计学差异（P<0.05）,蟑螂、尘螨、霉菌、豚草、屋尘和年龄组间有统计学差异（P<0.05）。不同临床症状与IgE阳性率有统计学差异(P<0.05),其中呼吸道过敏症状组IgE阳性率最高（48.30 %）,不同症状组间主要过敏原都是尘螨。屋尘阳性患者均合并尘螨阳性,其中70.93 %的患者表现出了呼吸道过敏症状。结论：尘螨、屋尘是盐城地区未成年过敏性疾病患者最主要的吸入性过敏原,研究血清过敏原分布,对未成年人过敏性疾病的预防、诊疗具有重要意义。     

Influence of Specific Immunotherapy on the Activity of Human T Lymphocyte Kv1.3 Voltage-Gated Potassium Channels in Insect Venom Allergic Patients

Kv1.3 channels play an important role in T lymphocytes function. CD4⁺ and CD4⁺CD25⁺ T cells are two broad categories of T cells that are critically involved in the immunoresponse to allergens and that are also a major target for allergen immunotherapy. The aim of the study was to evaluate the effects of venom immunotherapy (VIT) on the activity of Kv1.3. channels on noncultured subsets: CD4⁺ and CD4⁺CD25⁺ T cells of insect venom allergic patients. Eleven patients with allergic reactions to bee or wasp venoms participated in the study. The patients were provided VIT according to the ultrarush protocol. CD4⁺ and CD4⁺CD25⁺ T cells were isolated from peripheral blood mononuclear cells of VIT-treated patients by an immunomagnetic method. We used the whole-cell patch clamp technique to investigate the whole potassium chord conductance (gK) of Kv1.3. channels in CD4⁺ and CD4⁺CD25⁺ T cells of venom-sensitive patients before and during the course of VIT. The conductance of Kv1.3. channels on CD4⁺CD25⁺ T cells decreased during the course of VIT. On day 0 it was 0.054 ± 0.07 [nS], and on day 70 it was 0.008 ± 0.09 [nS] (P = 0.03). The observed decrease of the gK of the Kv1.3 channels in the subpopulation of activated T cells may contribute to T cell tolerance and functional unresponsiveness of these cells to allergen in the early stages of VIT.     

Pimecrolimus Is a Potent Inhibitor of Allergic Reactions to Hymenopteran Venom Extracts and Birch Pollen Allergen In Vitro

Pimecrolimus (Elidel, SDZ ASM 981) is an anti-inflammatory and immunomodulatory 33-epichloro-derivative of macrolactam ascomycin, with low potential for affecting systemic immune responses compared with other calcineurin inhibitors, cyclosporin A and tacrolimus. Despite numerous studies focused on the mechanism of pimecrolimus action on mast cells, only the single report has addressed pimecrolimus effects on other typical FcεRI-expressing cells, the basophils. Patients allergic to birch pollen (n = 20), hymenopteran venoms (n = 23) and 10 non-allergic volunteers were examined. Primary human basophils pre-treated or not with 0.5–50 μMol pimecrolimus were exposed to various concentrations of recombinant Bet v 1a allergen, bee or wasp venom extracts and anti-IgE for 20 min, and then examined for the expression of CD45, CD193, CD203c, CD63 and CD164 using flow cytometry. The externalization of basophil activation markers (CD63 and CD164) was equally inhibited through pimecrolimus in cells activated by recombinant pollen allergen, hymenopteran venom extracts and anti-IgE. Although the individual response rate was subject to strong variation, importantly, pre-treatment with pimecrolimus lowered the number of activated basophils in response to any of the stimuli in the basophils from all patients. The inhibition was concentration-dependent; approximately half of the basophils were inhibited in the presence of 2.5 mMol pimecrolimus. Pimecrolimus is a valuable new tool for the inhibition of hyper-reactive basophils in patients with pollen allergy and a history of anaphylactic reactions to bee or wasp venoms. Further research should address short-term use of pimecrolimus in vivo in a wide spectrum of allergic diseases.     

Multimer technologies for detection and adoptive transfer of antigen-specific T cells

Identification and purification of antigen-specific T cells without altering their functional status are of high scientific and clinical interest. Staining with major histocompatibility complex (MHC)-peptide multimers constitutes a very powerful method to study antigen-specific T-cell subpopulations, allowing their direct visualization and quantification. MHC-peptide multimers, such as dimers, tetramers, pentamers, streptamers, dextramers and octamers have been used to evaluate the frequency of CD8⁺ T cells, specific for tumor/leukemia-associated antigens as well as for viral antigens, e.g., CMVpp65 and EBV-EBNA. Moreover, MHC-peptide multimers have been used for rapid and efficient ex vivo isolation and expansion of T cells. A recent development in the field of MHC-peptide multimers led to the purification of CD8⁺ T cells specific for leukemia antigens. This might help to select leukemia-specific donor lymphocyte infusions (DLIs), thus allowing dissection of the noxious graft-versus-host disease (GvHD) from beneficial anti-viral and even anti-leukemic effects. This review covers different types of MHC-peptide multimers and their applications, as well as the impact that multimers might have on further development of DLIs.     

实验比格犬群发性泌尿系统结石的诊治

目的寻找某实验比格犬繁育基地群发性泌尿系统结石的病因及其有效的防治措施。方法采用临床诊断、病理诊断、结石成分分析、饲料成分分析、回顾性调查分析等手段以及综合的处理措施。结果经分析发现该群发性泌尿系统结石是由肉粉引起的尿酸盐结石,通过碱化尿液、降低血尿酸和去除病因等方法后,全群得到了有效的治疗。结论该肉粉是引起此次群发性泌尿系统结石的主要原因,由尿酸盐引起的、未发生器质性病变的尿路结石症可以治愈。     

Regulation of Constitutive Neutrophil Apoptosis Due to House Dust Mite Allergen in Normal and Allergic Rhinitis Subjects

House dust mite (HDM) is a primary allergen in allergic rhinitis (AR) and asthma. Neutrophil apoptosis is associated with allergic diseases and innate immunity to infection. The present study examined how HDM affects constitutive neutrophil apoptosis in normal and AR subjects. Total IgE increased in AR subjects when compared to normal subjects, and patients with AR were HDM-specific IgE positive (+), which is specific IgE to Dermatophagoides pteronissinus and Dermatophagoides farinae. In normal and AR subjects, neutrophil apoptosis was inhibited by extract of Dermatophagoides pteronissinus (DP), but not by extract of Dermatophagoides farina (DF). Aprotinin (serine protease inhibitor) and E64 (cysteine protease inhibitor) have no effect on neutrophil apoptosis due to DP. The anti-apoptotic effect of DP was blocked by TLR4i, an inhibitor of TLR4, rottlerin, an inhibitor of PKCδ, PD98059, an inhibitor of ERK, and BAY-11-7085, an inhibitor of NF-κB. DP induced PKCδ, ERK, and NF-κB activation in a time-dependent manner. DP inhibited the cleavage of procaspase 3 and procaspase 9. The expression of IL-6, IL-8, TNF-α, G-CSF, GM-CSF, and CCL2 increased in the supernatant collected from the normal and AR neutrophils after DP treatment and the supernatant inhibited the apoptosis of normal and AR neutrophils. In summary, DP has anti-apoptotic effects on neutrophils of normal and AR subjects through the TLR4/PKCδ/ERK/NF-κB pathway, and this finding may contribute to solution of the pathogenic mechanism of allergic diseases triggered by DP.     

舌下特异性免疫治疗变应性鼻炎的临床疗效评价

目的：评价舌下特异性免疫治疗变应性鼻炎（allergicrhinitis,AR）的临床疗效,探讨提高AR疗效的治疗措施。方法：选择同期门诊及住院治疗的AR患者76例,在患者自愿的前提下,将患者分为对照组（n=40例）和观察组（n=36例）,对照组患者给予常规药物治疗措施,观察组患者在上述治疗措施的基础上加行舌下特异性免疫治疗,治疗12个月后比较两组患者变异性鼻炎症状评分、变异性鼻炎体征评分、临床疗效及不良反应的发生情况。结果：治疗前,两组患者变异性鼻炎症状评分与体征评分比较。差异均无统计学意义（P〉0．05）;治疗12个月后,两组患者变异性鼻炎症状评分与体征评分均较治疗前显著降低,差异具有统计学意义（P〈0．05）,且观察组患者变异性鼻炎症状评分与体征评分显著低于对照组,差异具有统计学意义（P〈0．05）。对照组和观察组的治疗总有效率分别为为87．5％和100．0％,差异具有统计学意义（P〈0．05）。此外,两组治疗期间不良反应的发生率比较差异无统计学意义（P〉0．05）。结论：舌下特异性免疫治疗治疗AR,其临床疗效确切且安全可靠,值得推广和深入研究。     

Designing and Modeling of Multi-epitope Proteins for Diagnosis of Toxocara canis Infection

International Journal of Peptide Research and Therapeutics - Serological investigation is the main method to achieve satisfactory results in Toxocara canis diagnosis. The accuracy of the native...     

Active Immunotherapy Used Alone for Maintenance of Patients with Acute Myeloid Leukaemia

A total of 32 patients suffering from acute myeloid leukaemia were initially treated with daunorubicin and cytosine arabinoside, and eight who achieved full remission were given a brief cytoreduction course of cyclophosphamide and thioguanine. Of these eight patients seven were then actively immunized with 10 irradiated allogeneic acute myeloid leukaemia cells and B.C.G. at weekly intervals. Six of these patients have survived in apparent good health for more than one year. Bone marrow changes suggestive of relapse were used as an indication for further short courses of chemotherapy, and except on single occasions in two different patients clinical relapse has been prevented. The average duration of first (bone marrow) remission appears to be comparable with the best achieved in trials using regular chemotherapy for maintenance, though criteria for determining relapse may be different. The rate of reinduction of remissions (bone marrow) in this series was high, with a subsequent increase in overall survival time. Possible explanations for the high rate of reinduction include, firstly, the effects of active immunization with specific leukaemia antigen; secondly, non-specific adjuvant effect; thirdly, avoidance of drug resistance; and, fourthly, early diagnosis of relapse by frequent bone marrow examinations.     

Allergen Challenge Induces Ifng Dependent GTPases in the Lungs as Part of a Th1 Transcriptome Response in a Murine Model of Allergic Asthma

According to the current paradigm, allergic airway inflammation is mediated by Th2 cytokines and pro-inflammatory chemokines. Since allergic inflammation is self-limited, we hypothesized that allergen challenge simultaneously induces anti-inflammatory genes to counter-balance the effects of Th2 cytokines and chemokines. To identify these putative anti-inflammatory genes, we compared the gene expression profile in the lungs of ragweed-sensitized mice four hours after challenge with either PBS or ragweed extract (RWE) using a micro-array platform. Consistent with our hypothesis, RWE challenge concurrently upregulated Th1-associated early target genes of the Il12/Stat4 pathway, such as p47 and p65 GTPases (Iigp, Tgtp and Gbp1), Socs1, Cxcl9, Cxcl10 and Gadd45g with the Th2 genes Il4, Il5, Ccl2 and Ccl7. These Th1-associated genes remain upregulated longer than the Th2 genes. Augmentation of the local Th1 milieu by administration of Il12 or CpG prior to RWE challenge further upregulated these Th1 genes. Abolition of the Th1 response by disrupting the Ifng gene increased allergic airway inflammation and abrogated RWE challenge-induced upregulation of GTPases, Cxcl9, Cxcl10 and Socs1, but not Gadd45g. Our data demonstrate that allergen challenge induces two sets of Th1-associated genes in the lungs: 1) Ifng-dependent genes such as p47 and p65 GTPases, Socs1, Cxcl9 and Cxcl10 and 2) Ifng-independent Th1-inducing genes like Gadd45g. We propose that allergen-induced airway inflammation is regulated by simultaneous upregulation of Th1 and Th2 genes, and that persistent unopposed upregulation of Th1 genes resolves allergic inflammation.     

特异性免疫不同方式给药治疗变应性鼻炎的临床效果观察

目的:研究特异性免疫不同方式给药治疗变应性鼻炎的临床效果及安全性。方法:选取2013年4月-2015年4月我院收治的80例变应性鼻炎患者为研究对象,按照给药方式的不同分为对照组与观察组,对照组给予变应原疫苗皮下免疫治疗,观察组给予变应原滴剂舌下免疫治疗,比较两组患者的治疗效果、症状积分、体征积分、RQLQ评分的改善情况与不良反应的发生情况。结果:观察组患者治疗1年后症状积分、体征积分、RQLQ评分均显著低于对照组(P0.05),但总有效率显著高于对照组(P0.01),两组患者均无严重不良反应发生,对照组患者局部不良反应的发生率明显高于观察组(P0.01)。结论:采用皮下免疫法对变应性鼻炎的治疗效果明显优于舌下免疫治疗,可有效控制患者症状和体征,且安全性更高。     

MHC Class II-Restricted Presentation of the Major House Dust Mite Allergen Der p 1 Is GILT-Dependent: Implications for Allergic Asthma

Gamma-interferon-inducible lysosomal thiol reductase (GILT) is known to reduce disulfide bonds present in proteins internalized by antigen presenting cells, facilitating optimal processing and presentation of peptides on Major Histocompatibility Complex class II molecules, as well as the subsequent activation of CD4-positive T lymphocytes. Here, we show that GILT is required for class II-restricted processing and presentation of immunodominant epitopes from the major house dust mite allergen Der p 1. In the absence of GILT, CD4-positive T cell responses to Der p 1 are significantly reduced, resulting in mitigated allergic airway inflammation in response to Der p 1 and house dust mite extracts in a murine model of asthma.